SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication

Christina A. Higgins, Benjamin E. Nilsson-Payant, Boris Bonaventure, Andrew P. Kurland, Chengjin Ye, Tomer M. Yaron, Jared L. Johnson, Prithy Adhikary, Ilona Golynker, Maryline Panis, Oded Danziger, Brad R. Rosenberg, Lewis C. Cantley, Luis Martínez-Sobrido, Benjamin tenOever, Jeffrey R. Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifiesinfected cells to optimize virus replication. One such modificationis the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatorycytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identifiedputative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies.

Original languageEnglish
Issue number4
StatePublished - Jul 2023
Externally publishedYes


  • MAPK11
  • SARS-CoV-2
  • p38 kinases
  • p38β
  • phosphoproteomics
  • proteomics


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